title: CXCR4 and CCR5 ligands cooperate in monocyte and lymphocyte migration and in inhibition of dual-tropic (R5/X4) HIV-1 infection.
abstract: One of the most important functions of chemokines and their receptors is the regulation of directional migration of leukocytes within tissues. In specific tissue compartments, cells are exposed to multiple chemokines presented in complex dimensional and temporal patterns. Therefore, a leukocyte requires the mechanisms to integrate the various directional signals it receives from different chemoattractants. In this study, we report that CCL3, CCL5, and CCL8, three potent mononuclear cell chemoattractants, are able to synergize with the homeostatic chemokine CXCL12 in the migration of CD14(+) monocytes, CD3(+) T-lymphocytes, or PHA-activated lymphoblasts. In addition, CCL5 augmented the CXCR4 ligand-driven ERK phosphorylation in mononuclear cells. Furthermore, the synergistic effect between CCL5 and CXCL12 in monocyte chemotaxis is inhibited in the presence of specific CCR1 antibody and AMD3100, but not by maraviroc. In HIV-1 infection assays, a combination of CXCL12 and CCL5 cooperated to inhibit the replication of the dual-tropic (R5/X4) HIV-1 HE strain. Finally, although the dual-tropic HIV-1 strain was barely suppressed by AMD3100 or maraviroc alone, HIV-1 infection was completely blocked by the combination of these two receptor antagonists. Our data demonstrate the cooperation between CCL5 and CXCL12, which has implications in migration of monocytes/lymphocytes during inflammation and in HIV-1 infection.
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium. mieke.gouwy@rega.kuleuven.be
authors.forename: Mieke
authors.initials: M
authors.lastname: Gouwy
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Nele
authors.initials: N
authors.lastname: Berghmans
authors.forename: Christophe
authors.initials: C
authors.lastname: Vanormelingen
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4